Cell membrane receptors which transmit signals to the intracellular region via the activation of heterotrimeric GTP binding protein are generally referred to as “G protein-coupled receptor”. All members of the G protein-coupled receptor known to date are sometimes referred generally to as “seven transmembrane receptor”, because they form a super family having a common structure which has the extracellular amino terminus and intracellular carboxyl terminus and passes through the cell membrane seven times. The G protein-coupled receptor transmits information on various physiologically active substances from cell membranes to the intracellular region via activation of heterotrimeric GTP binding protein and subsequent changes in the intracellular second messengers induced. As the intracellular second messengers which are controlled by the heterotrimeric GTP binding protein, cAMP via adenylate cyclase, Ca++ via phospholipase C and the like are well known, and it has been revealed recently that many cellular proteins are their targets, such as the control of channels and activation of protein kinases via the heterotrimeric GTP binding protein (Gudermann, T. et al. (1997), Annu. Rev. Neurosci., 20, 399-427). The physiologically active substances that transmit information via the G protein-coupled receptor include various known physiologically active substances such as neurotransmitters, hormones, chemokine, lipid-originated signal transducers, divalent ions and proteases. Information by these physiologically active substances is transmitted to the intracellular region through their specific G protein-coupled receptor, respectively.
Several hundred types of G protein-coupled receptor have so far been cloned from eucaryote. Regarding human, hundred or more types of G protein-coupled receptor for corresponding endogenous ligands have been cloned and are regarded as targets of drugs for diseases. There are various diseases in which G protein-coupled receptor is the target, and there exist effective drugs which act upon G protein-coupled receptor, in the respective fields of central nervous system, circulatory organ system, inflammatory immune system, digestive organ system, motor organ system and urinary organ/reproductive organ system (Stadel, J. et al. (1997), Trends Pharmacol. Sci., 18, 430-437). This indicates that agonists or antagonists of G protein-coupled receptor have a high possibility of becoming a therapeutic agent of diseases, so that studies are being actively carried out on the discovery and identification of new G protein-coupled receptors.
Cloning of G protein-coupled receptor genes tends to start based on their structural homology in the super family in many cases, and a receptor having no correspondence to endogenous ligand is referred to as “the orphan G protein-coupled receptor”. In general, a ligand specific for the orphan G protein-coupled receptor has not been found, so that it was difficult to develop its agonist or antagonist. In recent years, however, it has been proposed to create a drug targeting for the orphan G protein-coupled receptor by combining the substantiated compound libraries and high performance high throughout screening (Stadel, J. et al. (1997), Trends Pharmacol. Sci., 18, 430-437).
That is, it is possible to screen an agonist for an orphan G protein-coupled receptor from a compound library by effective high throughput system of the measurement of cAMP and Ca++ which are second messengers of many G protein-coupled receptors, or the measurement of GTPase activity and G protein binding of GTPγS which are indexes of the activation of heterotrimeric GTP binding protein, so that it is possible to find specific agonists and antagonists making use of such compounds and furthermore to develop therapeutic drugs for certain diseases. Under such conditions, discovery of a novel G protein-coupled receptor capable of becoming a new therapeutic target of diseases is regarded as the most important step in creating a medicament which acts upon G protein-coupled receptors.
Among G protein-coupled receptors, there is a case in which a plurality of receptors are present for one endogenous ligand. Such receptors are referred to as receptor family, and each receptor is called subtype. Since all of the G protein-coupled receptors have a common structure which passes through the cell membrane seven times, 20 to 25% of amino acids are preserved mainly in the transmembrane region even in mutually independent G protein-coupled receptors, but when they form a receptor family, ratio of the amino acids preserved among its subtypes significantly increases to 35% or more, particularly to 60 to 80% among subtypes having high relevancy (Strader, C. D. et al. (1994), Annu. Rev. Biochem., 63, 101-132).
When development of a therapeutic drug for diseases is planned by targeting for an endogenous ligand wherein a receptor family is present, specificity of its subtypes becomes important in many cases. This is because actions upon other subtype than actions upon a subtype that mediates the main action of a drug lead to side effects in many cases. Accordingly, it is desirable to create a subtype-specific agonist or antagonist, but it is necessary to find a means for detecting the subtype-specificity for that purpose. Currently, a method for constructing a system in which a gene of a subtype is cloned and its specificity is detected using a cultured cell line or the like which expresses the gene is generally used.
When a novel G protein-coupled receptor is used as the target of disease treatment, it is highly possible that the subtype-specificity is important, so that discovery of a receptor family is important also in the case of the novel G protein-coupled receptor. The homology of amino acid sequences among independent G protein-coupled receptors is 20 to 25% as a whole, but when they form a receptor family, the homology significantly increases in general in the family, so that it is possible to presume whether they form a family or not, by comparing homology between two G protein-coupled receptors. It is possible to find novel G protein-coupled receptors which form a family, making use of such a means, and when a novel G protein-coupled receptor family is discovered, it will open a way for developing a drug for disease therapy because of the possibility of creating a subtype-specific agonist or antagonist.
The central nervous system transmits and controls various kinds of information using physiologically active substances represented by neurotransmitters. The G protein-coupled receptor is taking an important role in the signal transduction and control. Since many types of G protein-coupled receptor are present in the central nervous system, they are used as important therapeutic targets for diseases, of the central nervous system. For example, it is considered that the G protein-coupled receptor of a neurotransmitter, dopamine, is a therapeutic target of schizophrenia (Seeman, P. et al. (1997), Neuropsychopharmacology, 16, 93-110), the G protein-coupled receptor of serotonin is that of depression (Cowen, P. J. (1991), Br. J. Psychiatry, 159 (Suppl. 12), 7-14), and the G protein-coupled receptor of neuro-peptide Y is that of eating disorder (Blomqvist, A. G. and Herzog, H. (1997), Trends Neurosci., 20, 294-298).
It is considered that a novel G protein-coupled receptor expressing in the central nervous system, preferably a human receptor, will lead to a candidate for a new therapeutic target of central nervous system diseases or to the elucidation of central nervous system functions. In addition, for the purpose of developing a subtype-specific drug, it is desirable also to find a family in the case of the novel G protein-coupled receptor expressing in the central nervous system. Though the gene of a receptor GPR27 obtained from a mouse, having high homology with the amino acid sequence of SREB1 which is one of the G protein-coupled receptors of the invention, and an amino acid sequence based on its gene sequence have been reported (O'Dowd, B. F. et al. (1998), Genomics, 47, 310-313), no information is available to date concerning gene sequence and amino acid sequence of a human receptor.